Submissions for variant NM_000179.3(MSH6):c.3768T>G (p.Tyr1256Ter)

dbSNP: rs63751058

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074926	SCV000108139	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000491038	SCV000580173	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	clinical testing	The p.Y1256* pathogenic mutation (also known as c.3768T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide position 3768. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or loss of MSH6 by immunohistochemistry (IHC) (Hampel H et al. Cancer Res, 2006 Aug;66:7810-7; Hampel H et al. Cancer Res., 2007 Oct;67:9603; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202271	SCV000616790	pathogenic	not provided	2020-12-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Hampel 2007, Goldberg 2014, Goodfellow 2015); This variant is associated with the following publications: (PMID: 16885385, 25430799, 26552419, 17909073)
Invitae	RCV000546623	SCV000624913	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1256*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with endometrial cancer and suspected Lynch syndrome (PMID: 16885385, 25430799, 26552419). ClinVar contains an entry for this variant (Variation ID: 89458). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491038	SCV001345238	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with endometrial cancer and Lynch Syndrome in the literature (PMID: 16885385, 17909073, 25430799, 26552419). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000202271	SCV003822205	pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450979	SCV004188202	pathogenic	Lynch syndrome 5	2023-08-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003460691	SCV004197595	pathogenic	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074926	SCV004835134	pathogenic	Lynch syndrome	2024-01-05	criteria provided, single submitter	clinical testing	The c.3768T>G (p.Tyr1256*) variant in the MSH6 gene is located on the exon 8 and introduces a premature translation termination codon (p.Tyr1256*), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancer (PMID: 25430799, 33393477, 26552419, 16885385). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 89458) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3768T>G (p.Tyr1256*) variant of MSH6 has been classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074926	SCV004848882	pathogenic	Lynch syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The p.Tyr1256Ter variant in MSH6 has been reported in three individuals with MSH6-related cancers (Hampel 2007 PMID: 17909073, Roberts 2018 PMID: 29345684). It was absent from large population studies. This variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89458). This nonsense variant leads to a premature termination codon at position 1256, which is predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202271	SCV000257278	pathogenic	not provided		no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483461	SCV004228779	not provided	Mismatch repair cancer syndrome 1; Lynch syndrome 5		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-20-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.